The aim of this project is to address the question of whether there is a common etiology in the observation of depressed myelin deposition in two clinically related metabolic diseases, phenylketonuria (PKU) and branched-chain ketoaciduria (BCKA). These diseases have several things in common, depressed myelin formation, depressed glutamine levels and elevated blood, urine and cerebrospinal fluid levels of amino and alpha- keto acids. In addition the applicant has observed inhibition of pyruvate (PD) and alpha-ketoglutarate (KD) decarboxylation by the alpha- ketoacids which are elevated in both diseases. From these and other data the applicant has proposed that in both PKU and BCKA, the depressed myelin formation may have a common etiology, and that this may be an indirect general depression of synthetic energy and precusors from pyruvate and Krebs cycle metabolism. The resolution of the above question is to be approached by first surveying the metabolites, that are known to accumulate in the untreated diseases, for their effect on pyruvate and alpha- keto-glutarate metabolism and cholesterol synthesis. Using the compounds that accumulate and KD and PD inhibit a more detailed study to determine their effect on the several converging reactions of myelin synthesis and on the biosynthesis of ATP. The data obtained from this study will be used to test and refine a metabolic model proposed for these diseases by the applicant from both preliminary data accumulated in his laboratory and current literature.